Base-catalyzed synthesis of 1-aryl-4-(aryl ethyl)piperazines from aromatic olefins and 1-arylpiperazines

ABSTRACT

A process for preparing a 1-aryl-4-(arylethyl)piperazine of the formula (I)                    
     by reacting a 1-arylpiperazine of the formula (II)                    
     with an aromatic olefin of the formula (III) 
     
       
         Ar′CR 1 ═CHR 2   (III) 
       
     
     in an inert solvent in the presence of at least one basic catalyst, where in the formulae (I) to (III) 
     Ar and Ar′ independently of one another are an aryl radical, selected from the group of the fused and unfused C 6 -C 22 -aromatics and the fused or unfused C 5 -C 22 -heteroaromatics which have at least one nitrogen, oxygen or sulfur atom in the ring; and 
     R 1  and R 2  independently of one another are a hydrogen atom, a C 1 -C 8 -alkyl radical or an aryl radical Ar.

This application is a 371 of PCT/EP98/08344, filed Dec. 19, 1998.

The present invention relates to a novel process for preparing1-aryl-4-(arylethyl)piperazines.

Arylpiperazines are, as building blocks for a large number ofpharmaceutically active compounds, of industrial interest. In thiscontext, 1-aryl-4-(arylethyl)piperazines are of particular importance asactive compounds in medicinal chemistry. Thus, this class of compoundsis the subject of a large number of patents and publications.

1-aryl-4-(arylethyl)piperazines are mainly prepared by reacting thecorresponding arylpiperazines with 1-arylethyl-2-bromide. Another routeis the reaction of anilines with N,N-bis-2-chloroethylanilines.

In both reaction routes, halogenated starting materials are used, givingstoichiometric amounts of salt by-products. The latter is ecologicallydisadvantageous. In addition, the alkylations are insufficientlyselective, so that product yields of only 50-70% are obtained.

It is an object of the present invention to provide a process forpreparing 1-aryl-4-(arylethyl)piperazines from simple starting materialsunder mild reaction conditions which can be carried out on an industrialscale and does not produce any salt by-products.

This object is achieved by a process for preparing a1-aryl-4-(arylethyl)piperazine of the formula (I)

by reacting a 1-arylpiperazine of the formula (II)

with an aromatic olefin of the formula (III)

Ar′CR¹═CHR²  (III)

in an inert solvent in the presence of at least one basic catalyst,where in the formulae (I) to (III)

Ar and Ar′ independently of one another are an aryl radical, selectedfrom the group of the fused and unfused C₆-C₂₂-aromatics and the fusedor unfused C₅-C₂₂-heteroaromatics which have at least one nitrogen,oxygen or sulfur atom in the ring; and

R₁ and R₂ independently of one another are a hydrogen atom, aC₁-C₈-alkyl radical or an aryl radical Ar.

It is furthermore possible to prepare the product of the formula (I) byextending the intermolecular coupling between the aromatic olefin of theformula (III) and the arylpiperazine of the formula (II) by anintramolecular amination of a corresponding compound.

It is an essential property of the process according to the inventionthat, for the first time, the arylpiperazines react with aromaticolefins under base catalysis, generally in good to very good yields offrom 90 to 99%. Salt by-products are not formed.

The inert solvent can be selected from the group consisting of aromatichydrocarbons, such as toluene, xylenes, anisole, tetraline, andaliphatic ethers, such as tetrahydrofuran, dimethoxyethane, dioxane,tetrahydropyran, formaldehyde acetals. Examples of the aryl radical Arare phenyl, naphthyl, anthryl, phenanthryl and diphenyl, pyridyl,furfuryl or pyrazolyl radicals.

The basic catalyst can be selected from the group consisting of

alkali metal and alkaline earth metal hydrocarbons, such as, forexample, phenyllithium or butyllithium;

alkali metal and alkaline earth metal amides, such as, for example,potassium amide, potassium dimethylamide, potassium diisopropylamide,potassium propylamide, potassium isopropylamide, sodium amide, sodiumdimethylamide, sodium diisopropylamide, sodium propylamide, sodiumisopropylamide, lithium amide, lithium dimethylamide, lithiumdiisopropylamide, lithium propylamide or lithium isopropylamide;

alkali metals and alkaline earth metals, such as, for example, sodium orpotassium; and

alkali metal hydrides, such as, for example, sodium hydride or potassiumhydride.

In addition, the basic catalyst used can also be a mixture of thecatalysts described above with one another or with alkali metal oralkaline earth metal silazides, such as, for example, potassiumhexamethyidisilazide, sodium hexamethyldisilazide, lithiumhexamethyidisilazide.

Preferred basic catalysts are alkali metal and alkaline earth metalhydrocarbons and alkali metal and alkaline earth metal amides.

Studies have shown that alkali metal amides and alkali metalhydrocarbons are particularly effective catalysts.

The basic catalyst can be employed directly in the form of one of thecompounds mentioned or similar compounds. However, in some cases it isadvantageous, owing to the stability of the basic catalyst, to preparethe active compound in situ from suitable precursors.

The basic catalyst can be employed in an amount of from 0.01 to 20 mol%, in particular from 0.1 to 5 mol %, based on the arylpiperazine of theformula (II).

The aryl radicals Ar or Ar′ in the formulae (I) and (III) can,independently of one another, have up to 8 identical or differentsubstituents from the group consisting of hydrogen, fluorine, chlorine,bromine or iodine atoms and C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₈-acyloxy,HO—, O₂N—, CN—, HOC(O)—, HC(O)—, HOS(O)₂—, R⁴S(O)₂—, R⁴S(O)—, H₂N—,R⁴N(H)—, R⁴ ₂N—, R⁴C(O)N(H)—, R⁴C(O)—, (OCH)HN—, Ar″C(O)—, ArC(O)O—,CF₃—, H₂NC(O)—, R⁴OC(O)C(H)═C(H)—, Ar″₂P(O)—, R⁴ ₂P(O)—, R⁴ ₃Si— orheteroaryl radicals having 5 or 6 atoms in the aryl ring, where R⁴ is aC₁-C₁₂-alkyl radical and Ar″ is selected from the group of the fused orunfused C₆-C₂₂-aromatics and the fused or unfused C₅-C₂₂-heteroaromaticswhich have at least one nitrogen, oxygen or sulfur atom in the ring.

The reaction is carried out at temperatures of from 0 to 200° C., inparticular at from 10 to 150° C. and preferably at from 20 to 120° C.

Owing to the tendency to undergo oligomerization or polymerization sidereactions, it may, in the case of some aromatic olefins of the formula(III), be advantageous to add a polymerization inhibitor. For thispurpose, it is possible to employ the customary polymerizationinhibitors, such as, for example, p-quinone.

The examples below serve only to illustrate the process.

EXAMPLES

General Section

All reactions are carried out with exclusion of air and water under anatmosphere of argon in a 30 ml pressure tube from Aldrich with Teflonseal. The solvents used were dried by customary methods known from theliterature and stored over 4 Å molecular sieves under an atmosphere ofargon. Before use, all starting materials were dried and likewise storedover 4 Å molecular sieves and under protective gas. ¹H-NMR (400 MHz) and¹³C-NMR (100 MHz) spectra are calibrated by means of the chemical shiftsof the solvents used.

General Procedure (Hereinbelow GP):

In a pressure tube, heated thoroughly and flushed with argon, 2.22 mmolof substituted N-arylpiperazine and 50 μl of hexadecane are initiallycharged and dissolved in 4 ml of THF. In the closed pressure tube, thesolution is cooled with a mixture of isopropanol and dry ice for 30 min,and 5 mol % of n-butyllithium n-BuLi (1.6 molar n-BuLi solution inn-hexane) are then added under a stream of argon, whereupon the color ofthe solution in each case turns to yellow to orange. The mixture is thenstirred for a further 30 min until it has warmed to ambient temperatureagain. 2.22 mmol of olefin are then added, and the reaction mixture isstirred vigorously at ambient temperature for 5 min. The mixture isheated at an oil bath temperature of 120° C. for 20 h and, aftercooling, hydrolyzed with 2 ml of water. To isolate the product, theturbid two-phase system is admixed with 5 ml of 1 M hydrochloric acidand 5 ml of methylene chloride. The aqueous phase is separated off andthe organic phase is extracted three times with in each case 5 ml of 1 Mhydrochloric acid, and all aqueous phases are then combined andneutralized by addition of sodium carbonate. The neutral solution isextracted five times with in each case 5 ml of methylene chloride, andall organic phases are combined, and then washed repeatedly with waterand dried over magnesium sulfate, and the solvent is removed underreduced pressure. Final isolation of the product is carried out bycolumn chromatography.

Example 1

According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and2.22 mmol (=0.23 g=0.25 ml) of styrene are reacted with 5 mol % (=0.111mmol=70 μl) of n-BuLi solution. Column-chromatographic separation withethyl acetate/n-hexane (3:1) gives the product1-(4-fluorophenyl)-4-(2-phenyl-1-ethyl)piperazine as a light-brownsolid.

Yield 99% of theory Molecular weight 284.38 g/mol R_(f) value 0.53(ethyl acetate/hexane 3:1)

¹H-NMR (400 MHz, CDCl₃, 25° C.): δ=2.55-3.30 (m, 12H, aliphat. H);6.80-6.95 (m, 4H, arom. arylpiperazine-H); 7.10-7.25 (m, 5H, arom.phenyl-H). ¹³C-NMR (100 MHz, CDCl₃, 25° C.): δ=34.0 (—CH₂-phenyl); 50.6(—(CH₂)₂—N—CH₂—); 53.6 (—(CH₂)₂—N—CH₂—); 60.8 (—(CH₂)₂—N-aromatic);115.8-116.0 (d, ²J_(C,F)=22 Hz, —CH—C—F); 118.2-118.3 (d, ³J_(C,F)=8 Hz,—CH—CH—C—F); 126.5; 128.8; 129.1; 140.5 (quart.-phenyl); 148.3 (quart.C—N—); 156.4-158.8 (d, ¹J_(C,F)=239 Hz, C—F). GC-MS: m/e=284 (M⁺], 207[M⁺-phenyl], 193 [M⁺—CH²-phenyl], 150, 122, 70,

Example 2

According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and2.22 mmol (=0.30 g=0.30 ml) of para-methoxystyrene are reacted with 5mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographicseparation with ethyl acetate gives the product1-(4-fluorophenyl)-4-[2-(4-methoxyphenyl)-1-ethyl]piperazine as alight-yellow solid.

Yield 77% of theory Molecular weight 314.41 g/mol R_(f) value 0.60(hexane/ethyl acetate 3:1)

¹H-NMR (400 MHz, CDCl₃, 25° C.): δ=2.55-2.80 (m, 8H,—(CH₂)₂—N—CH₂—CH₂—); 3.07-3.16 (m, 4H, —(CH₂)₂—N-aromatic); 3.72 (s, 3H,—OCH₃); 6.75-6.80 (d, ²J=8.50 Hz, 2H, —CH—C—OCH₃); 6.80-6.95 (m, 4H,—CH—CH—C—F); 7.06-7.12 (d, ²J=8.50 Hz, —CH—CH—C—OCH₃). ¹³C-NMR (100 MHz,CDCl₃, 25° C.): δ=34.1 (—CH₂—C-phenyl); 50.5 (—(CH₂)₂—N—CH₂—); 53.6(—(CH₂)₂—N—CH₂—); 55.7 (OCH₃); 61.1 (—CH₂—N-aromatic); 114.3(—CH—C—OCH₃); 115.8-116.0 (d, ²J_(C,F)=22 Hz, —CH—C—F); 118.2-118.3 (d,³J_(C,F)=8 Hz, —CH—CH—C—F); 125.3 (—CH—CH—C—OCH₃); 130.0 (quart.C-phenyl); 156.4-158.4 (d, ¹J_(C,F)=199 Hz, —C—F). GC-MS: m/e=314 (M⁺],193 [M⁺—CH₂-phenyl—OCH₃], 150, 122, 95 [phenyl-F⁺].

Example 3

According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and2.22 mmol (=0.34 g) of 2-vinylnaphthalene are reacted with 5 mol %(=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographicseparation with ethyl acetate/n-hexane (1:1) gives the product1-(4-fluorophenyl)-4-[2-(2-naphthyl)-1-ethyl]piperazine as alight-yellow solid.

Yield 84% of theory Molecular weight 334.44 g/mol R_(f) value 0.59(hexane/ethyl acetate 1:1)

¹H-NMR (400 MHz, CDCl₃, 25° C.): δ=2.51-2.73 (m, 6H, —(CH₂)₂—N—CH₂—);2.92-3.01 (m, 2H, —(CH₂)₂—N—CH₂—CH₂—); 3.03-3.15 (m, 4H,—(CH₂)₂—N-aromatic); 6.79-6.93 (m, 4H, —CH—CH—C—F); 7.27-7.32 (dd,²J=8.0 Hz, ³J=1.5 Hz, 1H, aromatic H); 7.34-7.42 (m, 2H, aromatic H);7.57-7.62 (s, 1H, aromatic H); 7.68-7.77 (m, 3H, aromatic H). ¹³C-NMR(100 MHz, CDCl₃, 25° C.): δ=34.1 (—CH₂-phenyl); 50.6 (—(CH₂)₂—N—CH₂—);53.6 (—(CH₂)₂—N—CH₂—); 60.7 (—CH₂—N-aromatic); 115.8-116.0 (d,²J_(C,F)=22 Hz, —CH—C—F); 118.2-118.3 (d, ³J_(C,F)=8 Hz, —CH—CH—C—F);125.7-128.8 (aromatic C); 132.5, 134.0 (quart. C-naphthyl); 138.0(quart. —CH₂—C-naphthyl); 148.3 (quart. C—N—); 156.4-158.8 (d,¹J_(C,F)=239 Hz, C—F). GC-MS: m/e=334 (M⁺], 193 [M⁺—CH₂-naphthyl], 150,122, 95 [phenyl-F⁺], 70,

Example 4

According to GP, 2.22 mmol (=0.39 g) of 1-(3-methylphenyl)piperazine and2.22 mmol (=0.23 g=0.25 ml) of styrene are reacted with 5 mol % (=0.111mmol=70 μl) of n-BuLi solution. Column-chromatographic separation withethyl acetate gives the product4-(2-phenyl-1-ethyl)-1-(3-tolyl)piperazine as a light-brown solid.

Yield 99% of theory Molecular weight 280.41 g/mol R_(f) value 0.66(hexane/ethyl acetate 3:1)

¹H-NMR (400 MHz, CDCl₃, 25° C.): δ=2.24 (s, 3H, —CH₃); 2.57-2.66 (m, 6H,—(CH₂)₂—N—CH₂—); 2.76-2.83 (m, 2H, —(CH₂)₂—N—CH₂—CH₂—); 3.13-3.20 (m,4H, —(CH₂)₂—N-aromatic); 6.60-6.71 (s and 2 d, 3H, ²J=8.00 Hz,—N-aromatic-H); 7.06-7.10 (t, ²J=8.00 Hz, 1H, —N-aromatic-H); 7.10-7.25(m, 5H, —CH₂-phenyl-H). ¹³C-NMR (100 MHz, CDCl₃, 25° C.): δ=22.2 (—CH₃);34.0 (—CH₂-phenyl); 49.6 (—(CH₂)₂—N—CH₂—); 53.8 (—(CH₂)₂—N—CH₂—); 60.9(—CH₂—N-aromatic); 113.6, 117.3, 121.1, (C-tolyl); 126.5, 128.8, 129.1(C-phenyl); 129.3 (C-tolyl); 139.2 (quart. C—CH₃); 140.6 (quart.C-phenyl); 151.7 (quart. C—N). GC-MS: m/e=280 [M⁺], 189 [M⁺—CH₂-phenyl],146, 91 [phenyl-F⁺], 70,

Example 5

According to GP, 2.22 mmol (=0.51 g) of1-(3-trifluoromethylphenyl)piperazine and 2.22 mmol (=0.23 g=0.25 ml) ofstyrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution.Column-chromatographic separaton with ethyl acetate/n-hexane (1:1) givesthe product 4-(2-phenyl-1-ethyl)-1-(3-trfluoromethylphenyl)piperazine asa yellow oil.

Yield 89% of theory Molecular weight 334.38 g/mol R_(f) value 0.62(hexane/ethyl acetate13:1)

¹H-NMR (400 MHz, CDCl₃, 25° C.): δ=2.62-2.78 (m, 6H, —(CH₂)₂—N—CH₂—);2.85-2.96 (m, 2H, —(CH₂)₂—N—CH₂—CH₂—); 3.26-3.38 (m, 4H,—(CH₂)₂—N-aromatic); 7.08-7.41 (m, 9H, aromatic H). ¹³C-NMR (100 MHz,CDCl₃, 25° C.): δ=34.1 (—CH₂-phenyl); 49.2 (—(CH₂)₂—N—CH₂—); 53.6(—(CH₂)₂—N—CH₂—); 60.1 (—CH₂—N-aromatic); 112.6-112.7 (q, ³J_(C,F)=4 Hz,—CH—CH—C—CF₃); 115.3-115.5 (q, ³J_(C,F)=4 Hz, —N—C—CH—C—CF₃); 119.1;120.8-128.9 (q, ¹J_(C,F)=273 Hz, —CF₃); 126.7, 129.0, 129.2 (C-phenyl);130.1; 131.4-132.6 (q, ²J_(C,F)=19 Hz, —C—CF₃); 140.6 (quart. C-phenyl);151.9 (quart. C—N—). GC-MS: m/e=334 [M⁺], 243 [M⁺—CH₂-phenyl], 200, 172,145 [phenyl-CF₃ ⁺], 105, 91, 70,

Example 6

According to GP, 2.22 mmol (=0.43 g) of 1-(2-methoxyphenyl)piperazineand 2.22 mmol (=0.23 g=0.25 ml) of styrene are reacted with 5 mol %(=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographicseparation with ethyl acetate/n-hexane (1:2) gives the product1-(2-methoxyphenyl)-4-(2-phenyl-1-ethyl)piperazine as a yellow oil.

Yield 95% of theory Molecular weight 296.41 g/mol R_(f) value 0.48(hexane/ethyl acetate 1:1)

¹H-NMR (400 MHz, CDCl₃, 25° C.): δ=2.62-2.89 (m, 6H, —(CH₂)₂—N—CH₂—);2.80-2.89 (m, 2H, —(CH₂)₂—N—CH₂—CH₂—); 3.07-3.19 (m, 4H,—(CH₂)₂—N-aromatic); 3.37 (s, 3H, —OCH₃); 6.83-7.03 (m, 4H,arylpiperazine-H); 7.17-7.33 (m, 5H, phenyl-H). ¹³C-NMR (100 MHz, CDCl₃,25° C.): δ=34.0 (—CH₂-phenyl); 51.5 (—(CH₂)₂—N—CH₂—); 53.8(—(CH₂)₂—N—CH₂—); 55.7 (—OCH₃); 61.0 (—CH₂—N-aromatic); 111.6, 118.6,121.4, 123.3 (C-aromatic-arylpiperazine); 126.5, 128.8, 129.1(C-phenyl); 140.7 (quart. C-phenyl); 141.7 (quart. C—N—); 152.7 (quart.C—OCH₃). GC-MS: m/e=296 [M⁺], 205 [M⁺—CH₂-phenyl], 190[M⁺—CH₃—CH₂-phenyl], 162, 120, 105, 91, 70,

Example 7

According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and2.22 mmol (=0.31 g=0.28 ml) of 4-chlorostyrene are reacted with 5 mol %(=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographicseparation with ethyl acetatein-hexane gives the product1-(4-fluorophenyl)-4-[2-(4-chlorophenyl)-1-ethyl]piperazine as alight-yellow solid.

Yield 98% of theory Molecular weight 318.83 g/mol R_(f) value 0.53(ethyl acetate)

¹H-NMR (400 MHz, CDCl₃, 25° C.): δ=2.51-2.82 (m, 6H, —(CH₂)₂—N—CH₂—);3.09 (dd, 2H, —(CH₂-phenyl); 3.12-3.29 (m, 4H, —(CH₂)₂—N-aromatic);6.76-6.95 (m, 4H, F-arylpiperazine-H); 7.08 (d, 2H, J=8.50 Hz, aromaticH); 7.17-7.23 (m, 2H, aromatic H). ¹³C-NMR (100 MHz, CDCl₃, 25° C.):δ=32.9 (—CH₂-phenyl); 50.2 (—(CH₂)₂—N—CH₂—); 53.2 (—(CH₂)₂—N—CH₂—); 60.1(—CH₂—N-aromatic); 115.4-115.6 (d, J=22 Hz, —CH—C—F); 117.8-117.9 (d,J=8 Hz, —CH—CH—C—F); 128.5, 130.0 (C-chloroaromatic); 131.8 (quart.C—Cl); 138.7 (quart. C-chloroaromatic); 147.9 (quart. C—N—); 156.0158.4(d, J=238 Hz, —C—F). GC-MS: m/e=318 [M⁺], 193 [M⁺—CH₂—Cl-phenyl], 178,150, 122, 95, 70, 42, 28,

EA Calc. C 67.81 H 6.32 N 8.79 Found C 67.57 H 6.45 N 8.97

Example 8

According to GP, 2.22 mmol (=0.36 g=0.34 ml) of phenylpiperazine and2.22 mmol (=0.26 g=0.30 ml) of 3-methylstyrene are reacted with 5 mol %(=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographicseparation with ethyl acetate/n-hexane (3:1) gives the product1-phenyl-4-[2-(3-methylphenyl)-1-ethyl]piperazine as a light-yellowsolid.

Yield 93% of theory Molecular weight 280.42 g/mol R_(f) value 0.77(hexane/ethyl acetate 3:1)

¹H-NMR (400 MHz, CDCl₃, 25° C.): δ=2.52 (s, 3H, —CH₃); 2.82-2.95 (m, 6H,—(CH₂)₂—N—CH₂—); 3.01 (m, 2H, —(CH₂)₂—N—CH₂—CH₂—); 3.48 (m, 4H,—(CH₂)₂—N-aromatic); 7.03-7.27 (m, 6H); 7.39 (t, 1H, J=7.00 Hz); 7.48(t, 2H, J=7.50 Hz). ¹³C-NMR (100 MHz, CDCl₃, 25° C.): δ=21.4 (—CH₃);33.5 (—CH₂-phenyl); 49.2 (—(CH₂)₂—N—CH₂—); 53.2 (—(CH₂)₂—N—CH₂—); 60.6(—CH₂—N-aromatic); 116.0; 119.7; 125.7; 126.8; 128.3; 129.1; 129.5;138.0 (quart. C-phenyl); 140.1 (quart. C—CH₃); 151.3 (quart. C—N—).GC-MS: m/e=280 [M⁺], 151, 137, 129,

Elemental analysis Calc. C 81.38 H 8.63 N 9.99 Found C 81.01 H 8.48 N9.84

Example 9

According to GP, 2.22 mmol (=0.36 g=0.34 ml) of phenylpiperazine and2.22 mmol (=0.26 g=0.29 ml) of α-methylstyrene are reacted with 5 mol %(=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographicseparation with ethyl acetate/n-hexane (3:1) gives the product1-phenyl-4-(2-phenylpropyl)piperazine as a light-yellow solid.

Yield 86% of theory Molecular weight 280.42 g/mol R_(f) value 0.70(hexane/ethyl acetate 3:1)

¹H-NMR (400 MHz, CDCl₃, 25° C.): δ=1.33 (d, 3H, J=7.00 Hz, —CH₃);2.53-2.72 (m, 6H, —(CH₂)₂—N—CH₂—); 3.03 (sextet, 1H, J=7.00 Hz, —CH—);3.15-3.25 (m, 4H, —(CH₂)₂—N-aromatic); 6.86 (t, 1H, J=7.00 Hz,p-H-arylpiperazine); 6.93 (d, 2H, J=8.00 Hz, o-H-arylpiperazine);7.20-7.35 (m, 7H). ¹³C-NMR (100 MHz, CDCl₃, 25° C.): δ=20.0 (—CH₃); 37.4(—CH-phenyl); 49.1 (—(CH₂)₂—N—CH₂—); 53.5 (—(CH₂)₂—N—CH₂—); 66.1(—CH₂—N-aromatic); 115.0; 119.5; 126.1; 127.2; 128.3; 129.0; 146.1(quart. C-phenyl); 151.4 (quart. C—N—). GC-MS: m/e=280 [M⁺], 175[M⁺—CH₃—CH-phenyl], 160 [M+—CH₃—CH-phenyl, —CH₃], 132, 104, 70, 56, 28,

Elemental analysis Calc. C 81.38 H 8.63 N 9.99 Found C 81.37 H 8.65 N9.82

Example 10

According to GP, 2.22 mmol (=0.36 g=0.34 ml) of phenylpiperazine and2.22 mmol (=0.26 g=0.29 ml) of β-trans-methylstyrene are reacted with 5mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographicseparation with ethyl acetate/n-hexane (3:1) gives the product1-phenyl-4-(1-methyl-2-phenylethyl)piperazine as a yellow solid.

Yield 71% of theory Molecular weight 280.42 g/mol R_(f) value 0.56(hexane/ethyl acetate 3:1)

¹H-NMR (400 MHz, CDCl₃, 25° C.): δ=0.97 (d, 3H, J=6.50 Hz, —CH₃); 2.42(dd, 1H, J=12.50 Hz, J=9.00 Hz, —CH₂—CH—); 2.76 (m, 4H, —(CH₂)₂—N—CH₂—);2.84 (m, 1H, —CH—CH₃); 3.00 (dd, 1H, J=13.00 Hz, J=4.00 Hz, —CH₂—CH—);3.19 (m, 4H, —(CH₂)₂—N-aromatic); 6.82 (t, 1H, J=7.00 Hz,p-H-arylpiperazine); 6.91 (d, 2H, J=8.00 Hz, o-H-arylpiperazine);7.11-7.27 m, 7H). ¹³C-NMR (100 MHz, CDCl₃, 25° C.): δ=14.4 (—CH₃); 39.4(—CH-phenyl); 48.5 (—(CH₂)₂—N—CH₂—); 49.6 (—(CH₂)₂—N—CH—); 61.3(—CH₂—N-aromatic); 116.1; 119.6; 125.8; 128.2; 129.1; 129.3; 140.5(quart. C-phenyl); 151.5 (quart. C—N—). GC-MS: m/e=280 [M⁺], 189[M⁺—CH₂-phenyl], 174 [M+—CH₂-phenyl, —CH₃], 160, 132, 120, 91, 56, 28.

Elemental analysis Calc. C 81.38 H 8.63 N 9.99 Found C 81.57 H 8.76 N9.75

What is claimed is:
 1. A process for preparing a1-aryl-4-(arylethyl)piperazine of the formula (I)

which comprises reacting a 1-arylpiperazine of the formula (II)

with an aromatic olefin of the formula (III) Ar′CR¹═CHR²  (III) in aninert solvent in the presence of at least one basic catalyst, where inthe formulae (I) to (III) Ar and Ar′ independently of one another are anaryl radical, selected from the group consisting of fused and unfusedC₆-C₂₂-aromatics and fused or unfused C₅-C₂₂-heteroaromatics which haveat least one nitrogen, oxygen or sulfur atom in the ring; R₁ and R₂independently of one another are a hydrogen atom, a C₁-C₈-alkyl radicalor an aryl radical Ar.
 2. The process as claimed in claim 1, wherein thebasic catalyst is an alkali metal amide, alkaline earth metal amide,alkali metal hydrocarbon or alkaline earth metal hydrocarbon.
 3. Theprocess as claimed in claim 1, wherein a mixture of at least two basiccatalysts is used.
 4. The process as claimed in claim 1, wherein thebasic catalyst is employed in an amount of from 0.01 to 20 mol % basedon the arylpiperazine of the formula (II).
 5. The process as claimed inclaim 1, wherein the aryl radicals Ar or Ar′ independently of oneanother have up to 8 identical or different substituents selected fromthe group consisting of a hydrogen atom, a fluorine atom, a chlorineatom, a bromine atom, an iodine atom, C₁-C₈-alkyl, C₁-C₈-alkoxy,C₁-C₈-acyloxy, HO—, O₂N—, CN—, HOC(O)—, HC(O)—, HOS(O)₂—, R⁴S(O)₂—,R⁴S(O)—, H₂N—, R⁴N(H)—, R⁴ ₂N—, R⁴C(O)N(H)—, R⁴C(O)—, (OCH)HN—,Ar″C(O)—, ArC(O)O—, CF₃—, H₂NC(O)—, R⁴OC(O)C(H)═C(H)—, Ar″₂P(O)—, R⁴₂P(O)—, R⁴ ₃Si— and heteroaryl radicals having 5 or 6 atoms in the arylring, R⁴ is a C₁-C₁₂-alkyl radical and Ar″ is fused or unfusedC₆-C₂₂-aromatics or fused or unfused C₅-C₂₂-heteroaromatics which haveat least one nitrogen, oxygen or sulfur atom in the ring.
 6. The processas claimed in claim 2, wherein a mixture of at least two basic catalystsis used.
 7. The process as claimed in claim 6, wherein the basiccatalyst is employed in an amount from 0.1 to 5 mol % based on thearylpiperazine of the formula (II).
 8. The process as claimed in claim7, wherein aryl radicals Ar or Ar′ independently of one another have upto 8 identical or different substituents selected from the groupconsisting of a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, an iodine atom, C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₈-acyloxy,HO—, O₂N—, CN—, HOC(O)—, HC(O)—, HOS(O)₂—, R⁴S(O)₂—, R⁴S(O)—, H₂N—,R⁴N(H)—, R⁴ ₂N—, R⁴C(O)N(H)—, R⁴C(O)—, (OCH)HN—, Ar″(O)—, ArC(O)O—,CF₃—, H₂NC(O)—, R⁴OC(O)C(H)═C(H)—, Ar″₂P(O)—, R⁴ ₂P(O)—, R⁴ ₃Si— andheteroaryl radicals having 5 or 6 atoms in the aryl ring, R⁴ is aC₁-C₁₂-alkyl radical and Ar″ is fused or unfused C₆-C₂₂-aromatics orfused or unfused C₅-C₂₂-heteroaromatics which have at least onenitrogen, oxygen or sulfur atom in the ring.
 9. The process as claimedin claim 1, wherein the reaction is carried out at a temperature from 0to 200° C.
 10. The process as claimed in claim 8, wherein the reactionis carried out at a temperature from 10 to 150° C.
 11. The process asclaimed in claim 10, wherein the reaction is carried out at atemperature from 20 to 120° C.